10-133528614-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000773.4(CYP2E1):c.311C>T(p.Pro104Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P104S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CYP2E1 NM_000773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

Genes affected

CYP2E1 (HGNC:2631): (cytochrome P450 family 2 subfamily E member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17692667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2E1	NM_000773.4	c.311C>T	p.Pro104Leu	missense_variant	2/9	ENST00000252945.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2E1	ENST00000252945.8	c.311C>T	p.Pro104Leu	missense_variant	2/9	1	NM_000773.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000180 AC: 45 AN: 250110 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000328

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000267 AC: 390 AN: 1461032 Hom.: 0 Cov.: 31 AF XY: 0.000253 AC XY: 184 AN XY: 726812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000569

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152322 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9 AN XY: 74482

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000276 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The c.311C>T (p.P104L) alteration is located in exon 2 (coding exon 2) of the CYP2E1 gene. This alteration results from a C to T substitution at nucleotide position 311, causing the proline (P) at amino acid position 104 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.050	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Benign	0.094
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.12	B;B
Vest4		0.48
MVP		0.71
MPC		0.89
ClinPred		0.16	T
GERP RS		-0.66
Varity_R		0.36
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs543855005; hg19: chr10-135342118;